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Background: Identification of mechanisms for pain/hyperalgesia following spinal cord injury requires long-term evaluation of individual subjects because of the variability in effect over time for humans. Methods: Rats were trained on an operant escape task that determined their preference for occupancy of a brightly lit compartment versus a dark compartment with a floor preheated to 10, 32 or 44.5 °C. Following determination of baseline preferences, the animals received extradural implantation of a small piece of polymer in the thoracic spinal canal. The polymer narrowed the spinal canal and compressed the spinal cord. Post-operative tests of escape preference were conducted over 23 weeks (experiments 1 and 2) and 62 weeks (experiment 3), permitting statistical evaluation of individual effects. Results: Spinal stenosis/compression produced hyperalgesia for cold and/or heat stimulation (17 animals; 77%), no post-operative change in sensitivity (4 animals) or hypoalgesia for cold or heat (2 animals). When hyperalgesia occurred, it developed gradually over 4 months. Following removal of the polymer in experiment 3, heat sensitivity returned to baseline levels for four of four animals that had been hyperalgesic when the polymer was in place, but cold hyperalgesia was retained for four of five animals. Overall, post-operative changes in cold and heat sensitivity were not strongly related, indicating that different mechanisms were responsible for enhanced sensitivity to 10 and 44.5 °C. Conclusions: Histology revealed that hyperalgesia occurred when there was: (1) damage to spinal white matter; or (2) cystic cavitation; or (3) compression and distortion of the spinal cord without an obvious loss of grey or white matter.

Temporal summation of heat pain during repetitive stimulation is dependent on C nociceptor activation of central N-methyl-d-aspartate (NMDA) receptor mechanisms. Moderate temporal summation is produced by sequential triangular ramps of stimulation that control skin temperature between heat pulses but do not elicit distinct first and second pain sensations. Dramatic summation of second pain is produced by repeated contact of the skin with a preheated thermode, but skin temperature between taps is not controlled by this procedure. Therefore relationships between recordings of skin temperature and psychophysical ratings of heat pain were evaluated during series of repeated skin contacts. Surface and subcutaneous recordings of skin temperatures revealed efficient thermoregulatory compensation for heat stimulation at interstimulus intervals (ISIs) ranging from 2 to 8 s. Temporal summation of heat pain was strongly influenced by the ISIs and cannot be explained by small increases in skin temperature between taps or by heat storage throughout a stimulus series. Repetitive brief contact with a precooled thermode was utilized to evaluate whether temporal summation of cold pain occurs, and if so, whether it is influenced by skin temperature. Surface and subcutaneous recordings of skin temperature revealed a sluggish thermoregulatory compensation for repetitive cold stimulation. In contrast to heat stimulation, skin temperature did not recover between cold stimuli throughout ISIs of 3–8 s. Psychophysically, repetitive cold stimulation produced an aching pain sensation that progressed gradually and radiated beyond the site of stimulation. The magnitude of aching pain was well related to skin temperature and thus appeared to be established primarily by peripheral factors.

We have previously shown that fibromyalgia (FMS) patients have enhanced temporal summation (windup) and prolonged decay of heat-induced second pain in comparison to control subjects, consistent with central sensitization. It has been hypothesized that sensory abnormalities of FMS patients are related to deficient pain modulatory mechanisms. Therefore, we conducted several analyses to further characterize enhanced windup in FMS patients and to determine whether it can be centrally modulated by placebo, naloxone, or fentanyl. Pre-drug baseline ratings of FMS and normal control (NC) groups were compared with determine whether FMS had higher pain sensitivity in response to several types of thermal tests used to predominantly activate A-delta heat, C heat, or cold nociceptors. Our results confirmed and extended our earlier study in showing that FMS patients had larger magnitudes of heat tap as well as cold tap-induced windup when compared with age- and sex-matched NC subjects. The groups differed less in their ratings of sensory tests that rely predominantly on A-delta-nociceptive afferent input. Heat and cold-induced windup were attenuated by saline placebo injections and by fentanyl (0.75 and 1.5 microg/kg). However, naloxone injection had the same magnitudes of effect on first or second pain as that produced by placebo injection. Hypoalgesic effects of saline placebo and fentanyl on windup were at least as large in FMS as compared to NC subjects and therefore do not support the hypothesis that pain modulatory mechanisms are deficient in FMS. To the extent that temporal summation of second pain (windup) contributes to processes underlying hyperalgesia and persistent pain states, these results indirectly suggest that these processes can be centrally modulated in FMS patients by endogenous and exogenous analgesic manipulations.

Exercise activates endogenous opioid and adrenergic systems, but attenuation of exper- imental pain by exercise has not been shown consistently. In this study, effects of exercise on tem- poral summation of late pain responses to stimulation of unmyelinated (C) nociceptors were assessed. When a preheated thermode was applied repetitively to glabrous skin of the hand in a series of brief contacts at rates of 0.2 to 0.5 Hz, the perceived intensity of late thermal sensations increased after successive contacts. This summation of pain sensations provides information regard- ing the status of central opioid and N-methyl-D-aspartate receptor systems. For normal subjects, tem- poral summation of late pain sensations was substantially attenuated when testing began 1.5 or 10 minutes after exercise. Individuals diagnosed with fibromyalgia syndrome (FMS) report generalized chronic pain that is increased after exercise. Therefore, we hypothesized that strenuous exercise would increase summation of late pain sensations in this cohort. Patients with FMS and control sub- jects exerted to similarly high metabolic rates, as shown by physiologic monitoring. Ratings of late pain sensations increased for patients with FMS after exercise, an effect opposite to a decrease in rat- ings for age/sex-matched control subjects. In contrast to this result for experimentally induced pain, clinical pain ratings were not substantially altered after strenuous exercise by patients with FMS.

Operant escape from nociceptive thermal stimulation of 13 Long-Evans rats was compared before and after lateral spinal hemisection, to determine whether this lesion configuration provides an appropriate preclinical model of the hyperalgesia that can be associated with human spinal cord injury. Escape from 44 °C and from 47 °C stimulation was not affected following sham spinal surgery but was significantly reduced over 20 weeks of postoperative testing following lateral spinal hemisection. This result is opposite to previous reports of enhanced reflex withdrawal in response to thermal stimulation of rats following lateral spinal hemisection. In addition, the latency of reflexive lick/guard responses to 44 °C was increased and the duration of lick/guard responding was decreased in the present study (hyporeflexia). Thus, previous assessments of simple withdrawal reflexes have described a hyperreflexia following lateral spinal hemisection that was not replicated by lick/guard testing, and postoperative escape responding revealed hypoalgesia rather than the increased pain sensitivity expected in a model of chronic pain.

The behavioral deficits produced by trimethyltin (TMT) are usually attributed to the hippocampal damage caused by this toxicant. The purpose of this experiment was to determine the effects of TMT administration on acquisition and reversal of a discrete trial light-dark discrimination. Acquisition of this task is impaired by hippocampal lesions but the effects of TMT on it are not known. Forty-five days after some of the rats were given one of three doses of TMT, adult, male Long-Evans rats were given 100 trials per day for 20 days to acquire a discrete trial lever press discrimination with lit cue lights located above the correct lever. At the end of this time the contingencies were reversed and the rats were given 30 more days of training. No significant group differences occurred during the first 20 days. A significant group effect was found for the 30 days of reversal training. The rats given the highest dose of TMT (6 mg/kg) obtained significantly more reinforcements during reversal training than the other groups. Because surgical hippocampal lesions generally impair both acquisition and reversal of visual discriminations, these data were unexpected and suggest that other factors than hippocampal damage enter into the behavioral effects of TMT.

Effects of excitotoxic injury to the thoracic gray matter on sensitivity to below-level nociceptive stimulation were evaluated for female and male Long–Evans rats. Operant escape and lick/guard (L/G) reflex responses to thermal stimulation were evaluated before and for 13–15 weeks after: 1) injections of quisqualic acid (QUIS) into the thoracic gray matter (T8–9), 2) laminectomy and spinal exposure and penetration without injection (sham) or 3) no surgical procedure (control). L/G responding to heat stimulation (44 °C) was unaffected for females and males following thoracic QUIS injections. Similarly, male escape performance was not significantly altered for 44 °C or 10 °C stimulation after QUIS injections or sham surgery. However, escape testing following QUIS and sham injections revealed increased heat sensitivity (44 °C) and decreased cold sensitivity (10 °C) for females. This selective effect is indicative of altered sympathetic activation by the thoracic injections. The effect of sham surgery suggests that female rats are vulnerable to ischemic injury during exposure and manipulation of the spinal cord. Escape from nociceptive heat and cold sensitivity of control males and females was unchanged over 13–15 weeks of testing.

This experiment determined the effects of transplantation of fetal hippocampus on the ability of male rats with hippocampal lesions to acquire versions of a radial arm maze that depended on either extramaze cues or intramaze cues for solution. Rats receiving transplants took significantly more trials than control rats to emit three consecutive errorless trials in the extramaze cue (spatial) variation of the maze. Rats with just hippocampal lesions never differed from any other group. No differences in this measure were found for the intramaze cue condition. Rats receiving transplants made more repeat entries into reinforced arms in both versions of the maze than control rats and more reentries into neverbaited arms in the spatial maze. Rats with hippocampal lesions failed to differ from any other group on this measure in the spatial maze, but were different from normal rats in the intramaze cue maze. These data suggest that in some tasks transplants of fetal tissue lead to greater behavioral impairment than lesions alone.

The first purpose of the present experiments was to make a detailed study of the effects of hippocampal lesions on self-grooming behavior in rats. Hippocampal lesions decreased total grooming time and almost eliminated complete sequential grooming patterns, but increased open-field activity. Both hippocampal and neocortical lesions altered grooming in response to sucrose spray. The second purpose of this study was to compare the effects of the neurotoxin trimethyltin (TMT) with those produced by surgical destruction of the hippocampus. High doses of TMT, which produced extensive cell loss in the hippocampus, increased activity in the open field, but only moderate doses of TMT altered grooming. The results of the present study indicate that surgical removal of a large part of the hippocampus can disrupt a sequential, unlearned behavior. Furthermore, the behavioral effects of TMT cannot always be attributed to its neurotoxic action on the hippocampus.

The environmental neurotoxin trimethyltin (TMT) destroys parts of the hippocampal formation as well as the entorhinal cortex but leaves the septal cholinergic projection to the hippocampus and dentate gyrus intact. In this study we measured choline acetyltransferase (ChAT) activity in micropunch samples of the dentate gyrus, the CA1 region of Ammon's horn, and the caudate-putamen as a measure of density of cholinergic innervation in control rats and rats exposed to 7 mg/kg TMT by means of gastric intubation. Three months after the rats were exposed to a single dose of TMT both the dentate gyrus and CA1 demonstrated significantly higher ChAT activity in TMT-exposed rats than in control rats. No differences were found between groups for the caudate-putamen samples. These results support the hypothesis that exposure to TMT causes reactive synaptogenesis in the cholinergic septohippocampal system.

PURPOSE. A redistribution of neurochemicals has been identi fled in the visual cortex of monkeys with laser-induced glau coma. Examined were functional, structural, and neurochemi cal changes to the retina, optic nerve, and central visual system in a nonhuman primate model of optic nerve head (ONH) ischemia caused by sustained unilateral administration of endothelin (ET)-1 to the optic nerve. METHOD. ET-1 or sham control solution was delivered by osmotic minipump to the retrolaminar region of one optic nerve of rhesus monkeys (Macaca mulatta) for IS years. ONH topography and blood flow velocity were serially studied with scanning laser tomography and laser Doppler flowmetry, respectively. Retinal and cortical electrophysiologic measurements from pattern-derived stimuli were obtained quarterly. Immunohistochemistry was used to identify the distribution of calbindin (CB) and c-Fos labeled neurons in the visual cortex areas V1 and V2, and lateral geniculate nucleus (LGN). Retinal ganglion cell counts and optic nerve axon density were determined by light microscopy. RESULTS. No significant changes in retinal and ONH morphology, ONH blood flow velocity, and retinal and cortical pattern-derived functional activity were detected. Measurement of CB-positive cell density in V1 and V2 showed a significant decrease in CB labeling to the contralateral side of the ET-1-treated eye (P < 0.04). CB-positive cells were present in the magnocellular layers of the LGN with no differences noticed between the ET-1- and sham-treated eyes. c-Fos-labeled neurons were found in striate area V1 and extrastriateV2 of both groups. No c-Fos labeling was observed in the LGN. CONCLUSIONS. Administering ET-1 to the orbital optic nerve alters neuronal metabolic activity in the visual cortex in rhesus monkeys. Metabolic activity reductions in the visual cortex precede the ability to detect functional and structural alterations in the retina, ONH, and visual cortex in this animal model.

Although individuals with fibromyalgia syndrome (FMS) consistently report wide-spread pain, clear evidence of structural abnormalities or other sources of chronic stimulation of pain afferents in the involved body areas is lacking. Without convincing evidence for peripheral tissue abnormalities in FMS patients, it seems likely that a central pathophysiological process is at least partly responsible for FMS, as is the case for many chronic pain conditions. Therefore, the present study sought to obtain psychophysical evidence for the possibility that input to central nociceptive pathways is abnormally processed in individuals with long standing FMS. In particular, temporal summation of pain (wind-up) was assessed, using series of repetitive thermal stimulation of the glabrous skin of the hands. Although wind-up was evoked both in control and FMS subjects, clear differences were observed. The perceived magnitude of the sensory response to the first stimulus within a series was greater for FMS subjects compared to controls, as was the amount of temporal summation within a series. Within series of stimuli, FMS subjects reported increases in sensory magnitude to painful levels for interstimulus intervals of 2-5 s, but pain was evoked infrequently at intervals greater than 2 s for control subjects. Following the last stimulus in a series, after-sensations were greater in magnitude, lasted longer and were more frequently painful in FMS subjects. These results have multiple implications for the general characterization of pain in FMS and for an understanding of the underlying pathophysiological basis.

Vierck, Charles J., Jr., Richard L. Cannon, Gentry Fry, William Maixner, and Barry L. Whitsel. Characteristics of temporal summation of second pain sensations elicited by brief contact of glabrous skin by a preheated thermode. J. Neurophysiol. 78: 992–1002, 1997. Temporal summation of sensory intensity was investigated in normal subjects using novel methods of thermal stimulation. A Peltier thermode was heated and then applied in a series of brief (700 ms) contacts to different sites on the glabrous skin of either hand. Repetitive contacts on the thenar or hypothenar eminence, at interstimulus intervals (ISIs) of 3 s, progressively increased the perceived intensity of a thermal sensation that followed each contact at an onset latency >2 s. Temporal summation of these delayed (late) sensations was proportional to thermode temperature over a range of 45–53°C, progressing from a nonpainful level (warmth) to painful sensations that could be rated as very strong after 10 contacts. Short-latency pain sensations rarely were evoked by such stimuli and never attained levels substantially above pain threshold for the sequences and temperatures presented. Temporal summation produced by brief contacts was greater in rate and amount than increases in sensory intensity resulting from repetitive ramping to the same temperature by a thermode in constant contact with the skin. Variation of the interval between contacts revealed a dependence of sensory intensity on interstimulus interval that is similar to physiological demonstrations of windup, where increasing frequencies of spike train activity are evoked from spinal neurons by repetitive activation of unmyelinated nociceptors. However, substantial summation at repetition rates of ≥0.33 Hz was observed for temperatures that produced only late sensations of warmth when presented at frequencies

Adult male Long-Evans rats were given 6 mg/kg trimethyltin (TMT). Rats were killed 1, 3, 7, 14, 21, 35, or 60 d later. An untreated control group was included. Brain sections were processed using film autoradiography to visualize in the hippocampus either total muscarinic receptor binding ([3H]quinuclidinyl benzilate; [3H]QNB), or M1 receptors ([3H]pirenzepine; [3H]PZ), or M2 receptors ([3H]oxotremorine-M; [3H]OXO-M). A reduction in [3H]QNB binding was found in CA1 and CA3c 7 d after TMT, but not in CA3a, b, or the dentate gyrus. [3H]PZ binding was decreased throughout Ammon's horn by 14 d after treatment. [3H]OXO-M binding decreased 1 d after exposure in CA1 and in all subfields of Ammon's horn by d 3. Neither [3H]PZ or [3H]OXO-M binding decreased in the dentate gyrus of TMT-treated rat at any time point. The temporal patterns of receptor loss may be explicable by reference to timing of fiber and cell body degeneration reported in previous studies and the regional differences may account for discrepancies between reports of either substantial decreases or no loss in hippocampal muscarinic receptors after TMT exposure.